Center for Chemical Methodology

Boston, MA, United States

Center for Chemical Methodology

Boston, MA, United States
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Giri R.,University of Minnesota | Goodell J.R.,Center for Chemical Methodology | Xing C.,University of Minnesota | Benoit A.,University of Minnesota | And 3 more authors.
Bioorganic and Medicinal Chemistry | Year: 2010

A series of substituted xanthenes was synthesized and screened for activity using DU-145, MCF-7, and HeLa cancer cell growth inhibition assays. The most potent compound, 9g ([N,N-diethyl]-9-hydroxy-9-(3-methoxyphenyl)-9H-xanthene-3-carboxamide), was found to inhibit cancer cell growth with IC50 values ranging from 36 to 50 μM across all three cancer cell lines. Structure-activity relationship (SAR) data is presented that indicates additional gains in potency may be realized through further derivatization of the compounds (e.g., the incorporation of a 7-fluoro substituent to 9g). Results are also presented that suggest the compounds function through a unique mechanism of action as compared to that of related acridine and xanthone anticancer agents (which have been shown to intercalate into DNA and inhibit topoisomerase II activity). A structural comparison of these compounds suggests the differences in function may be due to the structure of the xanthene heterocycle which adopts a nonplanar conformation about the pyran ring. © 2010 Elsevier Ltd. All rights reserved.

Ting A.,Center for Chemical Methodology | Goss J.M.,Center for Chemical Methodology | McDougal N.T.,Center for Chemical Methodology | Schaus S.E.,Center for Chemical Methodology
Topics in Current Chemistry | Year: 2010

Chiral organic Brønsted bases have emerged as highly efficient catalysts for enantioselective transformations. Since their early use in enantiomeric separation processes, chiral organic Brønsted base catalysis has advanced significantly to include both natural and designed catalysts. Insight into the mode of action of the organocatalysts has promoted modifications in catalyst structures to expand the application to numerous asymmetric reactions. Bifunctional catalysts, containing both Brønsted base and H-activating functionalities, have proven to be very applicable to an array of reaction types. The development of Brønsted base catalysts containing or not containing H-activating moieties, has greatly impacted asymmetric organocatalysis. This overview illustrates the recent developments in this emerging field. © 2009 Springer-Verlag Berlin Heidelberg.

Jones A.L.,Center for Chemical Methodology | Liu X.,Center for Chemical Methodology | Snyder J.K.,Center for Chemical Methodology
Tetrahedron Letters | Year: 2010

The asymmetric syntheses of two anticancer natural products, candenatenins B and C, are described, leading to a revision of the originally assigned stereochemistries. The syntheses follow a Diels-Alder/retro-Diels Alder strategy using a chiral anthracene auxiliary to access both targets with 90% ee. The inherent structural qualities of the auxiliary allow for both regio- and diastereoselective transformations. © 2010 Elsevier Ltd. All rights reserved.

Cencic R.,McGill University | Carrier M.,McGill University | Trnkus A.,McGill University | Porco Jr. J.A.,Center for Chemical Methodology | And 2 more authors.
Leukemia Research | Year: 2010

We have previously shown that inhibition of translation initiation, using the small molecule inhibitor silvestrol, induces apoptosis in a pre-clinical murine lymphoma model when combined with daunorubicin. Silvestrol blocks ribosome recruitment by targeting the RNA helicase, eIF4A, which is required for this process. Here we investigate the sensitivity of acute myelogenous leukemia (AML) cell lines to protein synthesis inhibition in combination with the standard cytotoxic agents daunorubicin, etoposide, and cytarabine. Silvestrol shows synergy with standard-of-care agents in AML cell lines and synergizes with ABT-737, a small molecule inhibitor of Bcl-XL and Bcl-2. The in vitro synergy between silvestrol and the cytotoxic drugs used in AML therapy provides a basis for in vivo evaluation of these combinations. © 2009 Elsevier Ltd. All rights reserved.

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